Xylazine (a nonopioid veterinary sedative and alpha-2 adrenergic agonist) is approved by the FDA only for use in animals (cats, dogs, horses, elk…) to relieve pain and facilitate handling and medical procedures. Although xylazine is not listed as a federally controlled substance for animals or humans although several states consider it to be a schedule III drug, it is increasingly being used as an adulterant in the illicit drug supply, particularly in heroin and illegally manufactured fentanyl. People who use these substances may not know that they have been exposed to xylazine.
Data from case investigations related to driving under the influence of drugs (DUID) and medico-legal death (2019-2021) found a high prevalence of xylazine in opioids, stimulants, phytocannabinoids, and benzodiazepines across 36 states and the District of Columbia. What’s more, the prevalence and geographic distribution of xylazine increased substantially over the course of the study. In high prevalence areas, it is likely that anyone using these substances will be exposed to xylazine.
The associated risks of repeated xylazine exposure in humans are serious. In fact, the Food and Drug Administration (FDA) issued a xylazine safety alert in 2022 to warn health care providers about the potential harms of any delays in the diagnosis or treatment of patients exposed to this dangerous adulterant. To try to curb unintentional exposures, the FDA restricted the importation of xylazine (and ingredients to manufacture it) in 2023.
The adverse effects of accidental or intentional exposure can include miosis, blurred vision, disorientation, sedation, respiratory depression, hypotension, bradycardia, hyperglycemia, coma, and death. In addition to these effects from acute xylazine toxicity, xylazine’s high acidity, vasoconstrictive effects, and/or central nervous system depression can lead to distinctive soft tissue injuries. With repeated exposure these can become so severe that surgical debridement, reconstruction, or amputation may be required. Such xylazine-associated wounds (XAWs) are increasingly found in patients with repeat exposure to adulterated drug supplies.
How can clinicians identify patients who have been exposed to xylazine-adulterated drugs?
First, it is crucial to ask all patients with opioid use disorder about skin wounds, which may not be disclosed to health care providers due to the overwhelming stigma associated with drug use. Xylazine-associated wounds typically appear within hours or days following exposure, beginning as small blisters or bruises on the extremities (but can appear elsewhere like the sternum or scalp) and then progressing quickly to larger areas with full-thickness necrosis or even exposed bone. Although such chronic wounds are more commonly associated with xylazine-adulterated opioids that are injected, non-injection routes have also been implicated. Consider xylazine exposure as part of the differential diagnosis especially in patients with severe, necrotic skin ulcerations.
Second, consider xylazine exposure as a possible contributor to opioid overdose that does not respond to naloxone. Although naloxone should be given for any suspected opioid overdose (including those with xylazine-adulterated opioids), naloxone will not reverse (or mitigate) the effects of xylazine. Management should include supportive measures in those who do not respond fully to naloxone and once stabilized involve a multidisciplinary team comprised of addiction medicine, wound care, infectious disease, and surgery. In addition, those who have been exposed to xylazine require supportive care such as airway management and supplemental oxygen.
Third, consider a urine xylazine test to confirm exposure to xylazine; standard toxicology screens do not detect this agent. Such testing would probably not be necessary in geographic areas where xylazine is ubiquitous in the local fentanyl supply. Multiple federal agencies and research organizations collect data that can be used to identify where xylazine exposure is most common, often through drug seizure analysis and reporting of overdose.
Fourth, consider xylazine exposure as a possible contributor to severe or protracted withdrawal symptoms that are not well-managed with traditional treatments for opioid use disorder, such as methadone or buprenorphine. Validated withdrawal scales may be considered as an adjunct to clinical assessment of opioid withdrawal severity. Scales include the Objective Opiate Withdrawal Scale, the Clinical Opiate Withdrawal Scale, the Clinical Institute Narcotic Assessment, and the Subjective Opiate Withdrawal Scale.
In sum, it is crucial to identify patients with opioid use disorder who have been exposed to xylazine-adulterated drugs as soon as possible to avoid delays in diagnosis and treatment. Be vigilant about potential xylazine toxicity in patients who do not fully respond to naloxone in the setting of overdose. Routinely consider the likelihood of xylazine exposure in geographic areas where xylazine is ubiquitous in the street-purchased drug pool. Look for skin wounds at all points of follow-up. And assess response to treatments used in the management of opioid use disorder so that, if inadequate, management for xylazine withdrawal can be provided. Doing so can reduce the risk of xylazine-associated skin necrosis and other complications associated with xylazine exposure.
